The Maillard reaction, non-enzymatic glycation, is initiated by the condensation of an amino group present in proteins with a compound containing a carbonyl group, generally a sugar. A multitude of products, referred to as “advanced glycation end-products” (AGEs), result from the latter stages of this complex process. The consequence of the formation of these AGEs is protein cross-linking. Such cross-links have been observed in long-lived proteins such as collagen, lens crystalline, fibronectin, tubulin, myelin, laminin, actin, hemoglobin, albumin and the lipids associated with low-density lipoproteins (LDLs). AGE-modified proteins increase progressively with age and it is believed that they contribute to the normal tissue remodeling. Moreover, enhanced formation and accumulation of AGEs have been linked to the development of cataracts (Nagaraj et al., J. Biol. Chem. (1996) 271, 19338), uraemia (Miyata et al., Kidney Int. (1999) 55, 389), atherosclerosis (Kume et al., Am. J. Pathol. (1995) 147, 654; Stitt et al., Mol. Med. (1997) 3, 617), Alzheimer's disease (Münch et al., Biochem. Soc. Trans. (2003) 31 (6), 1397; Lüth et al., Cerebral Cortex (2005) 15(2), 211), Parkinson's disease (Webster et al., Neurotoxicity Res. (2005)/(172), 95), inflammatory disease (Anderson et al., J. Clin. Invest. (1999) 104, 103), age-related rheumatic disorders and, above all, clinical complications of diabetes mellitus (Brownlee, M. Ann. Rev. Med. (1995) 461, 223; Brinkmann et al., J. Biol. Chem. (1998) 273, 18714). Diabetic patients whose glycemia is elevated and persistent have an increased level of cross-linked proteins, which leads to tissue damage via modification of the structure and function of the proteins involved. Moreover, AGEs bind to membrane receptors and stimulate cellular responses. Since Maillard's discovery at the beginning of the last century, it has been believed that glucose is the sugar that participates in the cross-linking reaction. More recently, however, attention has been focused on α-dicarbonyl compounds, such as methylglyoxal (MG), glyoxal (GO) and 3-deoxyglucosone (3-DG), as active crosslinkers in vivo and in vitro. It is believed that the principal source of MG is the non-enzymatic dephosphorylation of triose-dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, which are glucose metabolites. MG can also be formed by the spontaneous decomposition of triose phosphates or by the metabolism of threonine or acetone. Some studies have also confirmed the generation of α-dicarbonyls via glucose auto-oxidation. It is believed that α-dicarbonyls can be generated during the transformation of a ketoamine, known as the Amadori product, a key intermediate in the Maillard reaction. This ketoamine is itself generated by the transformation of the Schiff-base adduct, which is initially formed during the reaction of glucose with an amine. In addition, it has been reported that bacteria produce MG. Lipid peroxidation of polyunsaturated fatty acids also yields reactive carbonyl compounds, such as MG and GO and those characteristic of lipids, such as malondialdehyde (MDA) and 4-hydroxynonenal. In general, such highly reactive dicarbonyls bind to the amino, guanidine and sulfhydryl groups of proteins and irreversibly form AGEs such as Nε-(1-carboxyethyl)lysine (CEL), Nε-(1-carboxymethyl)lysine (CML), methylglyoxal-derived hydroimidazolone Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1), glyoxal-derived hydroimidazolone (G-H1), argpyrimidine, glyoxal-derived lysine dimer, 1,3-di(Nε-lysino)imidazolium salt (GOLD), and methylglyoxal-derived lysine dimer, 1,3-di(Nε-lysino)-4-methylimidazolium salt (MOLD). The in vivo mechanism of action of these α-dicarbonyl compounds has been studied in an effort to understand the progression of the Maillard reaction in the organism. In diabetic subjects, increased formation and accumulation of AGEs occurs, thus leading to a series of long-term complications of diabetes such as nephropathy, retinopathy, neuropathy, ulcers and microvascular and macrovascular complications (Bucala et al., Diabetes Reviews (1995) 3, 258; Ulrich et al., Recent Prog. Horm. Res. (2001) 56, 1; Porta et al., Diabetologia (2002) 45, 1617; Lorenzi et al., Diabetologia (2001) 44, 791; Ziegler et al., Int. Rev. Neurobiol. (2002) 50, 451; Thornallay, P. J. Int. Rev. Neurobiol. (2002) 50, 37; Chiarelli et al., Diab. Nutr. Metab. (2000) 13, 192). More particularly, renal tissue damage caused by AGEs leads to the progressive loss of renal functioning (Makita Z., et al., N. Eng. J. Med. (1991) 325, 836). Indeed, among diabetic patients (type 1 and type 2), plasma concentration of methylglyoxal proved to be two to six times higher than that of normal subjects (McLellan et al., Clin. Sci. (1994) 87, 21).
Oxidative stress is another factor associated with ageing and with the current criteria for chronic diseases such as diabetes, atherosclerosis and related vascular diseases, rheumatoid polyarthritis and uremia. Oxidative stress is defined as a significant imbalance between antioxidant and oxidant generation systems. An increase in oxidative stress can have a profound effect on the modification of lipoproteins and on transcription, as well as on the functioning and metabolism of cells. Oxidative stress can appear via several mechanisms associated with the overproduction of oxygen radicals, such as the auto-oxidation of glucose and of glycated proteins and the glycation of antioxidant enzymes. Indeed, it has been reported that MG generates reactive oxygen species (ROS) (free radicals) during glycation reactions. Thus, it can be said that oxidative stress and AGE formation are inseparably intertwined.
Normally, the glyoxalase system (glyoxalase I and glyoxalase II) and aldose reductase catalyze the detoxification of these α-dicarbonyls into D-lactate, glycolate and acetol. However, a dysfunction of this detoxification metabolism leads to an increase in the quantity of AGEs formed by highly reactive α-dicarbonyls in the organism.
Inhibition of AGE formation can delay the progression of the physiopathology of AGE-related diseases and improve quality-of-life during ageing. It can thus be assumed that the pharmacological scavenging of α-dicarbonyl compounds is a valuable therapeutic strategy in the prevention of complications of diabetes. A large number of documents exist concerning the fact that an early stage pharmacological intervention against the long-term consequences of cross-linking prevents the development of later complications of diabetes. Even if AGE-formation inhibitors can not cure the underlying pathological process, they should delay the development of complications resulting from the fundamental disorders. Among the drugs specifically developed as AGE-formation inhibitors, aminoguanidine (pimagedine, AG) is the most studied and most used agent. AG is a nucleophilic compound with two key reactive functions, namely the nucleophilic hydrazine function —NHNH2 and the α-dicarbonyl directing guanidine function —NH—C(═NH)NH2. These two functional groups bound together jointly form a reactive bifunctional scavenger of methylglyoxal, glyoxal and 3-desoxyglucosone (Brownlee, et al., Science (1986) 232, 1629). Although the beneficial effects of AG against the complications of diabetes have been largely confirmed in the diabetic rat model, AG is a well-known selective inhibitor of nitrogen monoxide (NO) and a clinical trial related to the prevention of the progression of diabetic nephropathy by AG was abandoned due to safety concerns (Oturai et al., APMIS (1996) 104, 259; Monnier, V. M. Arch. Biochem. Biophys. (2003) 419, 1). Pyridoxamine (pyridon) is another agent able to prevent complications in the diabetic rat with greater effectiveness than that of aminoguanidine, and it is able to scavenge lipid peroxidation products and α-dicarbonyl compounds (Metz et al., Archives of Biochemistry and Biophysics (2003) 419, 41). Metformin, an antihyperglycemic drug widely used in the management of type 2 diabetes, also reduces levels of methylglyoxal and glyoxal both in vivo and in vitro by forming triazepinones (Beisswenger et al., Diabetes Metab. (2003) 29, 6895). However, AG proved to be a much better scavenger (by a factor of 450) of methylglyoxal compared with metformin (Battah et al., Intern. Congress Series 1245 (2002) 355). Other compounds possessing AGE-formation inhibitory activity include D-penicillamine (Wondrak G et al., Biochem. Pharmacol. (2002) 63, 361), LR-90, methylene bis(4,4′-(2-chlorophenylureidophenoxyisobutyric acid)) (Rahbar et al., Arch. Biochem. Biophys. (2003) 419, 63), thiamin (Benfotiamine) (Stracke et al., J. Exp. Clin. Endocrinol. Diabetes (2001) 109, 330), carnosine (β-alanyl-L-histidine), a natural dipeptide widely distributed throughout mammalian tissues (Hipkiss A. R., Int. J. Biochem. Cell Biol. (1998) 30, 863), curcumin (Sajithlal et al., G. Biochem. Pharmacol. (1998) 56, 1607) another natural compound isolated from Curcuma longa, 2,3-diaminophenazine (NNC39-0028) (Soulis, et al., Diabetologia (1999) 42, 472). Given the marked impact of AGEs on quality-of-life during ageing, there remains a need to develop efficient agents that can scavenge highly reactive α-dicarbonyl compounds such as methylglyoxal, glyoxal and 3-desoxyglucosone and that have low cytotoxicity and low mutagenicity.